19-nor-9beta, 10alpha-steroids of the pregnane series



United States Patent 0 ce M Patented 3 375 260 I and 17-polsitions can be prepared by processes which can 19 N0R 9| filoajsTFjRo-lns OF THE be illustrated schematically as follows:

PREGNANE SERIES OH; CH;

Albert Bowers, Atherton, Califi, Pierre Crab'b, =Mex'ico (3:0 I

City, Mexico, and John Edwards, LosAltos, Califi, as 5 signors to Syntex Corporation, Panama, Panamamzcorporation of Panama No Drawing. Continuation-impart of application Sen-No. 210,211, July 16, 1962. This application Mar. 8, 1965, Ser. No. 438,069 v v V Claims priority, applic6a5tio1619'Mexico, Dec. 4, 1961, 2

10 Claims. (51. 260-3973) This application is a continuation-impart of our 430- pending US. patent application Ser. No. 210 ,2-11, filed .15 July 16, 1962 now abandoned. CH, OH:

This invention relates to novel cyclopentanopolyhydro- =0 l =0 phenanthrene derivatives and to processes for the .preparation thereof.

More particularly, this invention relates to novel steroid 0 compounds of the l9-norpregnane series having abnormal configuration at the centers of asymmetry of the steroid skeleton, and particularly at carbon atoms '9 and 1-0, which compounds can be represented by the following general formula: V

In this formula R represents hydrogen, an oEhYdl'OXYl group or an a-acyloxy group, X, X and X each repre-, sent hydrogen or methyl, with X being hydrogen when either X or X is methyl, Y represents hydrogen, fl-hydroxyl or a keto group, and the symbol 2 indicates that a methyl substituent on the 16-carbon atom can have either the ocor the fi-configuration.

The acyloxy and acyl groups referred to herein are prefably derived from hydrocarbon carboxylic acids contain- 50 ing less than 12 carbon atoms. These acids 'c'an be saturated or unsaturated (including aromatic), and-' can have straight or branched aliphatic, cycloaliphatic, cycloali phatic-substituted aliphatic and aromatic-substituted aliphatic chains. In addition, theycan be unsubstituted or substituted with one or more functional groups, such as hydroxyl, alkoxy or amino groups, halogen atoms, and the like. Included among such ester groups are acetate, trimethylacetate, t-"butylacetate, phenoxyacetate, a-rninoacetate, propionate, cyclopentylpropionate, .fl-chloropropionate, valerate, enanthate, undecenoate and benzoate groups. I

The novel 19-nor-9fi,10a-pregnane derivatives of the present invention which are unsubstituted at the 6, 16-

HaCO

In these formulas X has the same meaning as set forth hereinabove for Formula I, and the symbol 3 indicates that a hydroxyl group attached to the ll-carbon atom can have either the Otor [Si-configuration. o

In practicing the above-illustrated processes, where lamethyl derivatives are desired 1 methyl-17B-acetyl- A -estratrien-3-ol (1) is first dehydrogenated with a chlorinated quinone, preferably 2,3-dichloro-5,6-dicyano-1,4-'benzoquinone or tetraehloro p benzoquinone (chloranil) in solution in dioxane or t-butanol to give the corresponding A -dehydro steroid 2, i.e., 1-methyl-17/3- acety1- A -estratetraen-3-ol.

Treatment of this 9(11)-dehydro compound with dimethyl sulfatein acetone solution in the presence of potassium hydroxide gives the corresponding 3-methyl ether 3, i.e., 1-methyl-3-methoxy-175-acety1-A -estratetraene (3; X=methyl).

Where lunsubstituted derivatives are desired, A dehydroprogesterone (4) is dehydrogenated, preferably using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone' in dioxane solution for a period of time in the order of 6 to 10 hours, thus giving A -pregnatriene-3,2O-dione (5).

The thus-obtained pregnatriene is then reacted with zinc or zinc-copper couple in aqueous pyridine or ethylene glycol as solvent, preferably for 10 to 24 hours when zinc is used and for a shorter time, i.e., from 2 to 6 hours, when zinc-copper couple is used, to effect aromatization of the A ring, thus giving 17B-acetyl-A -estratetraen-S-ol (6).

Treatment of the resulting estratetraene with dimethyl sulfate in acetone solution in the presence of potassium hydroxide gives the corresponding 3-methyl ether 3, i.e., 3-methoxy acetyl A1I35(1),9(11) estratetraene (3; X=hydrogen).

Treatment of a 3-methoxy-l7fl-acetyl-A estratetraene 3 (X=hydrogen or methyl) with ethylene glycol in benzene solution in the presence of ptoluenesulfonic acid gives the corresponding ZO-ketal 7, e.g., 3 methoxy 20 cycloethylenedioxy 19 nor- A -pregnatetraene (7; X=hydrogen).

The thus-obtained ZO-ketal is treated with a stream of diborane in tetrahydrofuran solution for a period of time in the order of 1 to 3 hours, and the resulting organoboron compound is then treated with alkaline hydrogen peroxide to give the corresponding lla-hydroxy steroid 8, e.g., 3-methoxy-ZO-cycloethylenedioxy-l9-nor-A pregnatrien-l 111-01 (8; X=hydrogen) Oxidation-of the resulting lloc-hYCllOXY steroid with chromic acid in pyridine solution gives the corresponding ll-keto steroid 9, e.g., 3-methoxy-20-cycloethylenedioxy- 19-nor-A -pregnatrien-1l-one (9; X=hydrogen).

Upon treatment of this ll-one with a dilute solution of a strong base in a lower aliphatic alcohol, preferably 1% methanolic potassium hydroxide, at reflux temperature for 5-24 hours under an inert nitrogen atmosphere, the steric configuration at C-9 is inverted, thus producing the corresponding 9,3-steroid 10, e.g., 3-methoxy-20-cycloethylenedioxy-19-nor-9fi-A -pregnatrien-ll-one (10; X=hydrogen).

Where the ll-unoxygenated derivatives are desired, the 1l-keto function in this 96-1 l-keto steroid is eliminated by reduction under Wolfi-Kishner conditions, thus giving the corresponding ll-unoxygenated steroid 11, e.g., 3- methoxy 20 cycloethylenedioxy 19 nor 9B-A pregnatriene (ll; X=hydrogen).

Reduction of the resulting ll-unoxygenated steroid under Birch conditions, using lithium in liquid ammonia, gives the A -diene 12, e.g., 3-methoxy-20-cycloethylenedioxy-19-nor-9fi-A -pregnadiene (12; X=hydrogen).

Acid hydrolysis of this A -diene, preferably carried out using hydrochloric acid in methanol at reflux temperature, removes the protective groups at C-3 and C-20, thus producing the 19-nor-9fi,l0at-A -pregnene-3,20 dione 13, e.g., l9-nor-9 3,l0a-A -pregnene-3,20-dione itself (19-n0f-9/3,IOa-PIOgCStBIOnC, X=hydrogen).

Where the ll-oxygenated derivatives are desired, the 11- keto group in the 9fl-ll-keto steroid 10, e.g., 3-methoxy- 20 cycloethylenedioxy 19 nor-9/3-A -pregnatrienll-one (10; X=hydrogen) can be reduced, using lithium aluminum hydride or sodium borohydride, thus giving a mixture of llocand Il s-alcohols l4, e.g., 3-methoxy-20- cycloethylenedi0xy-19 nor-9fi-A -pregnatrien 11a- 01 and 3 methoxy-ZO-cycloethylenedioxy 19- nor 9 18- A -pregnatrien-1113-01 (14; X=hydrogen), which can either be separated chromatographically or by fractional crystallization at this point or used as such in the next step. I

Reduction of the resulting 11-hydr0xy steroids under Birch conditions, using lithium in liquid ammonia, gives the A -diene l5, e.g., 3-methoxy-20-cycloethylenedioxy-l9-nor-9B-A -pregnadien-11 (on and/or fl)-ol (1S; X=hydrogen).

Alternatively, reduction of both the ll-keto group and the aromatic A ring can be effected in one step by subditions.

The A -diene is then hydrolyzed, using hydrochloric acid in methanol, in the manner described hereinabove, to remove the protective groups at -3 and C-20, thus giving the 19-nor-9fl,10a-A -pregnen-11-ol-3,20-dione 16, e.g., 19-nor-9 p,10u-A -pregnen-11a-ol-3,20-dione and 19- nor-9 9,10a-A -pregnen-1lfl-ol-3,20-dione (16; X=hydrogen), which can be separated chromatographically or by fractional crystallization, if desired, to give the individual 10 ll-ols.

Oxidation of the thus-obtained lloz-Ol, 115-01 or a mixture thereof, using 8 N chromic acid in acetone solution, produces the corresponding ll-keto steroid 17, e.g., 19- nor-95,10a-A -pregnene 3,11,20 trione (17; X=hydrogen).

The novel l9-nor-l7a-hydroxyand -acy1oxy-9fi,10apregnane derivatives of the present invention which are unsubstituted at the 6- and 16-positions can be prepared by processes which can be illustrated schematically as follows: 1

jecting the 9,8-11-keto steroid 10 to Birch reduction conl HOM HaCO- I 27.

In these formulas X and the symbol 5 (when used with the ll-hydroxyl group) have the same meanings as set forth hereinabove for Formulas I and 14, respectively, and R represents hydrogen or an acyl group.

In practicing the above-illustrated processes, the starting material 8, e.g., 3-methoxy-20-cycloethylenedioxy-19- nor-A -pregnatrien-llu-ol (8; X=hydrogcn) obtained as described hereinabove, is hydrolyzed with ptoluenesulfonic acid in acetone to give the corresponding free ZO-one 18, e.g., 3-methoxy-19-nor-A -pregnatrien-l 1a-ol-20-one 18; X=hydrogen) A hydroxyl group is then introduced at the 17 a-position in this Ila-hYdIOXY steroid by the Gallagher method, i.e., by formation of the 20-enol acetate with concomitant acetylation of the llu-hydroxyl group, epoxidation of the C-17, 20-d'ouble bond with perbenzoic acid, and finally opening of the epoxide ring with potassium hydroxide in methanol, with simultaneous saponification of the 110:- acetoxy group, thus giving the corresponding 11a,17o-diOl- 20-one 19, e.g., 3-methoxy-19-nor-A -pregnatriene- 11a,17a-di0l-20-On6(19; X=hydrogen) Treatment of this 11a,l7u-diol-20-one with ethylene glycol in benzene solution in the presence of p-toluenesulfonic "acid gives the corresponding 20-ketal 20, e.g., 3- methoxy 20 cycloethylenediox'y 19 nor A pregnatriene-11a,l7a-di0l (20; X=hydrogen).

Oxidation of the lla-hydroxy group in the resulting 2G- ketal, using chromium trioxide in pyridine at room temperature, gives the corresponding ll-one 21, e.g., 3- methoxy ZO-cycloethylenedioxy-l9-nor-A -pregnatrien-17a-ol-11-one (21; X=hydrogen).

Upon treatment of the thus-obtained 1I-one with a dilute solution of a strong base in a lower aliphatic alcohol, preferably 1% methanolic potassium hydroxide, at reflux temperature for 5-24 hours under an inert nitrogen 7 atmosphere, the steric configuration at C-9 is inverted, thus producing the corresponding 9,8-steroid 22, e.g., 3- methoxy 2O cycloethylenedioxy 19-nor-9B-A pregnatrien-17a-ol-1l-one (22; X=hydrogen).

Where the ll-unoxygenated derivatives are desired, the ll-keto function in this 913-1 l-keto steroid is eliminated by reduction under Wolii-Kishner conditions, thus giving the corresponding ll-unoxygenated steroid 23, e.g., 3- methoxy 20- cycloethylenedioxy 19 nor-9B-A pregnatrien-17a-ol (23; X=hydrogen).

Reduction of the resulting ll-unoxygenated steroid under Birch conditions, using lithium in liquid ammonia, gives the A -diene 24, e.g., 3-methoxy-20-cycloethylenedioxy 19 nor 9fiA -pregnadien-17a-ol (24; X=hydro gen) Acid hydrolysis of this A -diene in the manner described hereinabove removes the protective groups at C-3 and (3-20, thus producing the 19-nor-9fi,10a-A -prcgnen- 17a-ol-3,20-dione 25, e.-g., l9-n0r-9B,lUa-A -p16gI16I1-17aol-3,20-dine itself (25; R and X=hydrogen).

Esterification of the l7a-hydroxy group in the thusobtained 1711-01 25 is effected with acid anhydrides in benzene solution in the presence of p-toluenesulfonic acid, followed by acid treatment of the acylation reaction mixture, e.g., using a 1-5% methanolic solution of concen trated hydrochloric acid and boiling for from about 1 hour to about 3 hours, to hydrolyze the 3-enol acylate grouping formed during the reaction and regenerate the A -3-keto structure. Thus, for example, by esterifying l9-nor-9B,l0u-A -pregnen-17a-ol-3,20-dione with acetic anhydride in benzene solution in the presence of p-toluenesulfonic acid, and then adding a 2% methanolic solution of concentrated hydrochloric acid to the acylation reaction mixture and boiling for 2 hours, the corresponding 17-monoacetate is obtained (25; R =acety1, X=hydrogen).

Where the ll-oxygenated derivatives are desired, the ll-keto group in the 9fi-11-keto steroid 22, e.g., 3-methoxy 2O cycloethylenedioxy-19-nor-9fl-A -pregnatrien-l7a-ol-1l-one (22; X=hydrogen) can be reduced, using lithium aluminum hydride or sodium borohydride, thus giving a mixture of 11aand llfi-alcohols 26, e.g., 3-methoxy 20 cycloethylenedioxy-l9-nor-9B-A pregnatriene-lla,17a-diol and 3 -methoxy-20-cycloethylenedioxy-19-nor-9fi-A pregnatriene-l15,-17a-di0l (26; X=hydrogen), which can either be separated chromatographically or by fractional crystallization at this point or used as such in the next step.

Reduction of the resulting ll-hydroxy steroids under Birch conditions, using lithium in liquid ammonia, gives the A -diene 27, e.g., 3-methoxy-20-cycloethylenedioxy-19-nor-9fl-A -pregnadiene-11(u and/or ,8), 17adiol (27; X=hydrogen).

Alternatively, reduction of both the ll-keto group and the aromatic A ring can be effected in one step by subjecting the 9fi-ll-keto steroid 22 to Birch reduction conditions.

The A diene is then hydrolyzed under acidic conditions in the manner described hereinabove to remove the protective groups at C-3 and (1-20, thus giving the 19-nor- 9B,10orA -pregnene-1lp,l7a-diol-3,20-dione 28, e.g., 19- nor 9,B,1Oa-A -pregnene-1la,17a-diol-3,20-dione and 19- nor-9fl,ltla-A -pregnene-l1B,17a-diol-3,20-dione (28; R and X=hydrogen), which can be separated chromatographically or by fractional crystallization to give the individual ll-ols.

' Esterification of the l7ahydroxy group in a l9-nor- 96,l0a-A -pregnene-llB,17a-diol-3,20-di0ne 28, e.g., l9- nor-9B,10a-A -pregnene-1lfl,l7a-diol-3,2O-dione itself (28; R and X= hydrogen) is effected by first reacting with an acid anhydride in benzene in the presence of p-toluenesulfonic acid to give the corresponding 3-enol acylate -11,- 17-diacylate, then treating with acid to hydrolyze the 3- enol acylate grouping, and finally hydrolyzing the thusobtained 11,17-diester with a 1-5% solution of sodium or potassium bicarbonate in aqueous methanol at 0-20 C. for 1-18 hours to selectively hydrolyze the ll-acyloxy group and give the 17-monoester. Thus, for example, by carrying out this procedure using acetic anhydride as the acylating agent, 19-nor-9 3,IOa-M-pregnene-l15,17a-diol- 3,20-dione l7-acetate (28; R =acetyl, X=hydrogen) is obtained.

The ll-keto steroids 29 are obtained by first oxidizing the llfl-hydroxy group in a l9-nor-9fi,lOa-A -pregnene- 11/3,17a-diol-3,20-dione 17-acylate 28, e.g., 19-nor-9fl,l0u- A -pregnene-l1fl,l7a-diol-3,20-dione l7-acetate (28; R acetyl, X=hydrogen), using chromium trioxide in pyridine or 8 N chromic acid in acetone solution, to give the corresponding ll-one 17-acylate 29, e.g., 19-nor-9fi,l0a- A -pregnen-l7a-ol-3,11,20-trione 17-acetate (29; R acetyl, X=hydro gen) The l7a-acyloxy group in the thus-obtained ll-one 17- acylate can then be hydrolyzed, using methanolic potassium hydroxide at refiux temperature for 5-12 hours under an inert nitrogen atmosphere, thus giving the free 1l-one-17a-ol 29, e.g., l9-nor-9fl,lOa-A -pregnen-17a-ol- 3,11,20-trione (29; R and X=hydrogen).

An alternate procedure for the preparation of the 3- methoxy-ZO-cycloethylenedioxy-19-nor-9B-A pregnatrien-17oc-ol-1 l-one intermediate 22 can be illustrated schematically as follows:

is inverted and the benzoyloxy group at C-3 is hydrolyzed, thus producing the 3-hydroxy-9fl-steroid 38, e.g., 20-cycloethylencdioXy-19-nor 9B A -pregnatrieue-3,- 17a-diol-11-0ne (38; X=hydrogen).

Treatment of this 3-hydroxy-9B-steroid with dirnethyl sulfate in acetone solution in the presence of potassium carbonate gives the corresponding 3-methyl ether 22, e.g., 3-methoXy-20-cycloethylenedioxy-19-nor 9B A pregnatrien-lh-ol-ll-one (22; X=hydrogen).

The novel 19-nor-9fi,10a-pregnane derivatives of the present invention which are substituted at the 6-, 16- and 17-positions can be prepared by processes which can be illustrated schematically as follows:

(llHzoH In these formulas X has the same meaning as set forth hereinabove for Formula I and B represents a benzoyl group. v Z

In practicing the above-illustrated process the starting material 30, Le, 17B-acety1-A -estratetraen-3-ol or l-methyl-17fi-acetyl-A -estratetraen-3-ol, obtained as described hereinabove, is treated with ethylene glycol in benzene solution in the presence of p-toluenesulfonic acid to give the corresponding 20-ketal 31, e.g. 20-cyc1oethylenedioxy-19-nor A pregnatetraen-3-ol-(31; X=hydrogen).

This ZO-ketal is treated with a stream of diborane in tetrahydrofuran solution in the manner described herein above, then treated with alkaline hydrogen peroxide, thus giving the Ila-01 32, e.'g., 20-cycloethylenedioxy-19-nor- A -pregnatriene-3-11a-diol (32; X=hydrogen).

Acid hydrolysis of the thus-obtained ZO-cycloethylenedlOXY-llu-Ol gives the corresponding ZO-keto steroid 33, e.g., l9-nor-A -pregnatriene-3,11a-diOl-20-one (33; X=hydrogen) g A hydroxyl group is then introduced at the 17a-position in this 3,11a-diol-20-one by the Gallagher method, thus giving the corresponding 3,11a,l7a-triol-20-one 34, c.g., 19-nor-A -pregnatriene-3,1'1a,17a-triol-20-one (34; X =hydrogen) V Ketalization of the 20-keto group in the resulting 3,1111,- 17a-triol-20-one in the manner described hereinabove gives the corresponding ZO-ketal 35, e.g., 20-cycloethylenedioxy- 19-nor-A -pregnatriene-3,11a,17a-triol (35; X=hydrogen).

By subjecting this 3,11a,17a-tri01 to the Schotten-Baumann reaction, i.e., using benzoyl chloride and aqueous sodium hydroxide at room temperature, the corresponding 3-benzoate 36, e.g., 20-cycloethylenedioxy-19-nor- 413,5(10) pregnatriene 3,11a,17u trio] 3-beuzoate (36; X=hydrogen), is obtained.

Oxidation of the lla-hydroxy group in the resulting 3- benzoate, using chromium trioxide in pyridine at room temperature, gives the corresponding ll-one 37, e.g., 20- cycloethylenedioxy-l9-nor-A pregnatriene 3,170:- diol-l l-one 3-benzoate (37; X=hydrogen).

Upon treatment of this ll-one with a dilute solution of a strong base in a lower aliphatic alcohol in the manner described hereinabove, the steric configuration at C-9 75 In these formulas R X and X have the same meanings as set forth hereinabove for Formulas 25 and I, with atleast one of X and X representing methyl.

In practicing the first of these processes (39 43), the starting material 39, i.e., 6amethyl-, l6a-methyl-, 165- methyl-, 6a,16ot-dimethylor 6n,16fi-dimethyl-19-nor-9fi; 10a-A -pregnene-17a-21-diol-3,20-dione, obtained as described in our aforementioned copending U.S. patent application or as described in our copending U.S. patent application Ser. No. 438,084, filed concurrently herewith, now abandoned, is reduced by first treating it with tosyl chloride in pyridine solution at C. and then refluxing the resulting 21-tosylate with sodium iodide in acetic acid for a period of time in the order of 2 hours, thus producing the corresponding 21 desoxy steroid 40, e.g., 6a-methyl- 19 nor 95,10a A -pregnen-17a-o1-3,20-dione (40; X =methyl, R and X =hydrogen).

The free 17a-hydroxy group in this 21 desoxy steroid can be esterified in the manner described hereinabove for compound 25. Thus, for example, esterification of 6c:- methyl-l9-nor-9B,10a-A -pregnen-l7ot-ol-3,2O dione with acetic anhydried in benzene in the presence of p-toluenesulfonic acid, followed by hydrolysis of the 3-enol acetate grouping with methanolic concentrated hydrochloric acid, gives the corresponding 17-acetate (40; R =acetyl, X =methyl, X =hydrogen) The free 17u-hydroxy group in this 21-desoxy steroid can also be eliminated by reaction with zinc dust in aqueous acetic acid, preferably aqueous 80% acetic acid, at reflux temperature for a period of time in the order of 10 hours, thus producing the corresponding 60v, 1611-, or 16fi-methyl or 6a,16fi-dimethyl-19-nor-9j3,10a'progesterone derivative 41, e.g., 6m-methyl-19-nor-A -pregnene- 3,20-dione (41; X =methyl, X =hydrogen).

Adrenal incubation of the thus-obtained compound according to the method described in U.S. Patent No. 2,671,752 to Zaffaroni produces the corresponding 11,3- hydroxy steroid 42, e.g., 6a-methyl-19-nor-9p,10a-A pregnen-11B-ol-3,20-dione (42; X =methyl, X =hydrogen).

Finally, oxidation of the llfi-hydroxy group in the resulting llfi-hydroxy steroid, using 8 N chromic acid in acetone solution, gives the corresponding ll-keto steroid 43, e.g., 6ot-methyl-19-nor-9/3,10a-A -pregnene- 3,11,20-trione (43; X =methyl, X =hydrogen).

In practicing the second of these processes, the starting material 44; i.e., 6a-methyl-, 16a-methyl-, 16,B-methyl-, 6a,16a-dimethyl- 0r 6a,l6B-dimethyl-19-nor-9,8,1Ou-A pregnene-l1B,17a,21-triol-3,20-dione, also obtained as described in our aforementioned copending U.S. patent application or as described in our copending U.S. Patent application Ser. No. 438,084, filed concurrently herewith, is reduced in the manner described herein-above for step 39 40, thus giving the corresponding 21-desoxy steroid 45, e.g., 6a-methyl-19-nor-9fl,lou-A -pregnene-11,8,17udiol-3,20-dione (45; X =rnethyl, R and X hydrogen).

The free 17a-hydroxyl group in this 11,8-hydroxy-21- desoxy steroid can be esterified in the manner described hereinabove for compound 28. Thus, for example, esterification of 6a-methyl-19-n0r-9p,10a-A -pregnene-115,170

21-trio1-3,20-dione or 6a-methyl 19 nor 95,1011 A pregnene-17a,21-diol-3,11,20-trione with acetic anhydride in benzene in the presence of p-toluenesulfonic acid, followed by hydrolysis of the 3-enol acetate grouping with methanolic concentrated hydrochloric acid and then bydrolysis of the thus-obtained 11,17-diester with aqueous methanolic sodium or potassium bicarbonate in the manner described hereinabove, gives the corresponding 17- acetate (45; R =acetyl, X =methyl, X =hydrogen).

The ll-keto steroids 46 are obtained by first oxidizing the llp-hydroxy. group in a 6a-methyl-, 16-methylor 60:, 16-dimethyl-19-nor-9B,10a A pregnene 116,170- diol-3,20-dione 17-acylate, using chromium trioxide in pyridine or 8 N chromic acid in acetone solution, to give the corresponding 11-one 17-acylate 46, e.g., 6a-methyl- 19-nor-9fl,10u-A -pregnen-17a-ol-3,11,20 trione 17 acetate (46; R =acetyl, X =methy1, X =hydrogen).

The 17x-acyloxy group in the thus-obtained 11-one 17- acylate can then be hydrolyzed, using methanolic potassium hydroxide in the manner described hereinabove, to give the free 11-one-17a-ol 46, e.g., 6oc-l1'l6thYl-19-I10f- 9fi,10a-A -pregnen-17a-ol 3,11,20 trione (46; R and X =hydrogen, X =methyl) The novel 19-nor-9;3,l0a-pregnane derivatives of the present invention represented by Formula I hereinabove are progestational agents having oral activity. In addition, they have anti-androgenic activity and are useful in fertility control in humans and animals.

In order that those skilled in the art can more fully understand the present invention, the following examples are set forth. These examples are given solely for the purpose of illustrating the invention, and should not be considered as expressing limitations unless so set forth in the appended claims.

Example I Twenty grams of A -dehydroprogesterone were added to 400 cc. of dioxane and 14 grams of 2,3-dichloro- 5,6-dicyano-1,4-benzoquinone, and the resulting reaction mixture was refluxed for 10 hours. Following this reaction period the reaction mixture was cooled, the 2,3-dichloro-5,6-dicyano-1,4 benzohydroqu'inone formed during the reaction was filtered off, and the filtrate was then evaporated to dryness. The resulting residue was dissolved in acetone, then filtered through 400 grams of alumina, and finally crystallized from acetone/hexane, thus giving A -pregnatriene-3,ZO-dione.

Example ll A mixture of 612 cc. of pyridine, 1388 cc. of water, 200 grams of zine dust and 10 grams of A -pregnatriene-3,20-dione was refluxed, with stirring, for 20 hours. Following this reaction period the zinc was filtered off and the filtrate was then crystallized to /3 its volume under reduced pressure and diluted with water. Next, the diluted filtrate was extracted with methylene dichloride, and'the resulting extract was washed with 5% hydrochloric acid, then with 5% sodium carbonate and finally with water until neutral, then dried over anhydrous sodium sulfate and evaporated to dryness. Chromatography of the resulting residue on 500 grams of alumina gave 1713- acetyl A estratetraen-3 01, identical to an authentic sample [Mills et al., I. Am. Chem. Soc., 82, 5882 (1960)].

Example III A mixture of 10 grams of l-methyl-17,8-acetyl-A estratrien-3-ol, cc. of dioxane and 12 grams 2,3-di chloro-5,6-dicyano-1,4-benzoquinone was refluxed under an inert nitrogen atmosphere for 24 hours. Following this reaction period the reaction mixture was worked up in the manner described in Exampe I hereinabove (chromatography of the residue obtained upon evaporation of the filtrate was carried out using 50 times itsweight of washed alumina), thus giving 1-methyl-17fi-acetyl-A estratetraen-3-ol.

13 Example IV A solution of 14 grams of potassium hydroxide in 7.5 cc. of water was added to a suspension of grams of 17,8- acetyl-A -estraterien-3-0l in 10 cc. of acetone, and the resulting mixture was treated dropwise, with stirring, with 8 cc. of dimethyl sulfate. Following this addition the reaction mixture was stirred for an additional 45 minutes, following which it was poured over a dilute solution of hydrochloric acid and the resulting precipitate was collected by filtration, washed with water until neutral and dried. Crystallization from chloroform/methanol gave 3-methoxy-17fi-acetyl-A estratetraene.

By repeating this procedure using 1-methyl-17fi-acetyl- A estratetraen-3-ol as the steroid starting material, the corresponding 3-methyl ether was obtained.

Example V A mixture of 5 grams of 3 methoxy-17fiacetyl- A -estratetraene, 125 cc. of anhydrous benzene, 25 cc. of ethylene glycol and 250 mg. of p-toluenesulfonic acid was refluxed for 8 hours, using a water separator to remove the water formed during the reaction. Following this reaction period the reaction mixture was washed with 5% sodium bicarbonate solution until neutral, then dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone/hexane gave 3-methoxy-2Ocycloethylenedioxy-l9-nor-A pregnatetraene.

By repeating this procedure in every detail but one, namely, using 1 methyl 3 methoxy 17 8 acetyl- A -estratetraene as the steroid starting material, 1 methyl 3 methoxy 2O cycloethylenedioxy-19-nor- A -pregnatetraene was obtained.

Example VI A stream of diborane was passed through a solution of grams of 3 methoxy 20 cycloethylenedioxy-19-nor- A -pregnatetraene in 375 cc. of anhydrous tetrahydrofuran for 3 hours, following which the reaction mixture was allowed to stand at room temperature overnight under anhydrous conditions. Following this reaction period excess diborane was destroyed by the addition of water, and the resulting solution was then cooled to 5 C. and treated dropwise with 750 ml. of sodium hydroxide in 6 cc. of water and 90 cc. of 35% hydrogen peroxide. This mixture was stirred for one hour, then neutralized with acetic acid and extracted with methylene dichloride. The resulting extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Chromatography of the resulting residue on 750 grams of washed alumina followed by crystallization of the solid fractions gave 3 methoxy-20cycloethylenedioxy19-nor- A -pregnatrien-lla-ol.

By repeating this procedure in every detail but one, namely, replacing 3 methoxy-20cycloethylenedioriy-l9- nor-A -pregnatetraene with the corresponding l-methyl steroid, lmethyl-3methoxy-20-cycloethylenedioxy-19-nor-A -pregnatrien-1la-ol was obtained.

Example VII A solution of 10 grams of 3methoxy-20-cycloethylenedioxy 19 nor-A -pregnatrien-1lot-o1 in 200 cc. of acetone was cooled to 0 C. under an inert nitrogen atmosphere and then treated, with stirring, with an 8 N solution of chromic acid (prepared by mixing 26 grams of chromium trioxide with 23 cc. of concentrated sulfuric acidwith water and then dried under vacuum, thus affording a crude product which, upon recrystallization from 'acetone/hexane, gave 3 methoxy-20?cycloethylenedioxy-19- nor-A -pregnatrien-1l one. 1 I

This procedure was then repeated using 1-methyl-3- methoxy 20-cycloethylenedioxy-19-nor-A -pregnatrien-lla-ol as the steroid starting material, thus giving l-methyl 3 methoxy 20 cycloethylenedioxy-19-nor- A pregnatrien-1l-one.

Example VIII A mixture of 5 grams of 3methoxy-20-cycloethylenedioxy-19-nor-A -pregnatricn-1l-one and 400 cc. of a 1% methanolic potassium hydroxide solution was refluxed for 24 hours under an inert nitrogen atmosphere. Following this reaction period water was added to the reaction mixture and the product was then extracted with methylene dichloride. The resulting extract was washed with water until neutral, then dried over anhydrous sodium sulfate and evaporated to dryness, thus giving 3-methoxy- 20-cycloethylenedioxy 19 nor-9fi-A -pregnatrienll-one.

By repeating this procedure using l-methyl-3-methoxy- 20-cycloethylenedioxy 19 nor-A -pregnatrien-11- one as the steroid starting material, the corresponding steroid was obtained.

Example IX A mixture of 2 grams of 3methoxy-ZO-cycloethylenedioxy-19-nor-9fl-A -pregnatrien 11 one, 2.4 cc. of ethylene glycol and 4 cc. of hydrazine hydrate was refluxed for 1 hour. Following this reaction period the reaction mixture was cooled, admixed with 2.4 grams of potassium hydroxide dissolved in 2.4 cc. of water, and then heated in an open flask until the temperature of the reaction mixture reached 200 C. At this point, a reflux condenser was attached and the reaction mixture was refluxed for 2 hours. Following this reaction period the reaction mixture was cooled, diluted with water and extracted with diethyl ether. The thus-obtained extract was washed with water, then dried over anhydrous sodium sulfate and evaporated to dryness. Chromatography of the resulting residue on neutral alumina, followed by recrystallization of the solid fractions from acetone/benzene, gave 3 -methoxy-ZO-cycloethylenedioxy-19-nor-9fi- A -pregnatriene.

By repeating this procedure using l-methyl-S-methoxy- 20-cycloethylenedioxy 19 nor-9B-A -pregnatrienll-one as the steroid starting material, 1-methyl-3-methoxy-20-cycloethylenedioxy-19-nor-9 S-A pregnatriene was obtained.

Example X A solution of 1.5 grams of 3methoxy-20-cycloethylenedioxy-19-nor-9fl-A pregnatriene in 200 cc. of anhydrous diethyl ether was cooled to -10 C. and then added, with stirring, to a solution of 2 grams of lithium metal in 220 cc. of liquid ammonia, and the resulting mixture was stirred for 30 minutes. At this point, 45 cc. of absolute methanol were cautiously added (until decolorization occurred) and the ammonia was then evaporated. Next, the reaction mixture was diluted with water and extracted with diethyl ether. The combined ether extracts were washed with water until neutral, dried over anhydrous sodium sulfate and evaporated to dryness, thus giving 3 methoxy 20 cycloethylenedioxy 19-nor-9B- A -pregnadiene.

By repeating this procedure using l-methyl-3-methoxy- 19-nor-9fl-A pregnatriene as the steroid starting material, the corresponding A -diene was obtained.

' Example XI The 3 methoxy 20 cycloethylenedioxy 19 nor-9 8- A -pregnadiene prepared as described in Example X hereinabove, dissolved in 60 cc. of methanol, was admixed with 30 cc. of 3 N hydrochloric acid, and the resulting reaction mixture was refluxed for 45 minutes. Following this reaction period the reaction mixture was poured into water and extracted with ethyl acetate. The resulting extract was washed with water until neutral, dried over anhydrous sodiumsulfate and evaporated to 15 dryness. Chromatography of the residue on 75 grams of washed alumina gave 19 nor 9B,l0a-A -pregnene-3,20- dione (l9-nor-9fl,IDOL-progesterone).

By repeating this procedure using the l-methyl-A diene prepared as described in Example X hereinabove as the steroid starting material, 1a-methyl-19-nor-9B,1011-41 pregnene-3 ,20-dione 1tx-methyl-19-nor-9p,loot-progesterone) was obtained.

Example XII A solution of 1 gram of 3-methoxy-ZO-cycloethylenedioxy-19-nor-9fl-A -pregnatrien-1l-one in 30 cc. of anhydrous tetrahydrofuran was slowly added, with stirring, to a suspension of 1 gram of lithium aluminum hydride in 50 cc. of anhydrous tetrahydrofuran, and the resulting reaction mixture was refluxed for 2 hours. Following this reaction period the reaction mixture was cooled and excess lithium aluminum hydride was destroyed by the addition of 5 cc. of ethyl acetate and 2 cc. of water. Next, a saturated solution of sodium sulfate and solid sodium sulfate were added, the inorganic material was filtered off and washed with hot ethyl acetate, and these washings were added to the filtrate. The filtrate was then evaporated to dryness and the resulting residue was crystallized from acetone/hexane, thus giving a mixture of 3 a methoxy 20 cycloethylenedioxy 19 nor-913- A -pregnatrien-1lot-01 and 3-methoxy-20-cycloethylenedioxy-19-nor-9p-A '5 -pregnatriene-1 -01.

This procedure was then repeated using 1-methyl-3- methoxy cycloethylenedioxy 19 nor-9311 pregnatrien-ll-one as the steroid starting material, thus giving a mixture of l-methyl-3-methoxy-20-cycloethylenedioxy 19 nor 9B M51500) pregnatrien-lla-ol and 1 methyl 3 methoxy 20 cycloethylenedioxy 19- nor-9B-A -pregnatrien-1 15-01.

Example XIII By repeating the procedure of Example X hereinabove using the mixtures of llaand llfi-ols prepared as described in Example XII hereinabove, the corresponding A -dienes, namely, 3-rnethoxy-20-cycloethylenedioxy- 19-nor-9 8-A l -pregnadien-l1(a and 3)-ol and l-methyl 3 methoxy-ZO-cycloethylenedioxy-l9-nor-9/3-A pregnadien-ll(a and p)-ol, respectively, were obtained.

Example XIV By repeating the procedure of Example XI hereinabove using the mixtures of A -di6Il-11(cc and ,8)-0ls prepared as described in Example XIII hereinabove as the steroid starting materials, the corresponding 19-no'r- 9fl,l0a-steroids, namely, 19- nor-9p,10a-A -pregnen-11aol-3,20-dione and 19-nor-9B,1Oa-A -pregnen-1lB-ol 3,20- dione, and 1a-methyl-l9-nor-95,10ix-A -pregnen 11a ol- 3,20dione and 1a-methyl-19 nor-9fi,10ot-A -pregnen-11(3- ol-3,20-dione, respectively, were obtained, and these mixtures were then separated into the individual 110aand 11,6-ols by chromatography on alumina.

Example XV 19 nor 95,1004 A pregnen 115 ol-3,20-dione and 1a methyl 19 nor 9,8,10a A pregnen -115 {01- 3,20-dione were oxidized, using 8 N chromic acid in ace tone in the manner described in Example VII hereinabove, thus giving 19 nor 9fl,l0ot-A -pregnene-3,11,20 trione and la-rnethyl-l9-nor-9,B,10a-A -pregnene-3,l1,20- trione, respectively.

Example XVI Ten grams of 3 methoxy 19 nor A pregnatetraen-ZO-one were converted into the corresponding ZO-ketal, i.e., 3-methoxy-20-cycloethylenedioxy-19- nor-A -pregnatetraene, by reaction with ethylene glycol in benzene solution in the presence of p-toluenesulfonic acid in the manner described in Example V hereinabove.

The thus-obtained ZO-ketal was treated with diborane,

16 and then with alkaline hydrogen peroxide, in the manner described in Example VI hereinabove, thus giving 3-methoxy 2O cycloethylenedioxy-l9-nor-A -pregnatrienlion-O1. I

This lla-ol, dissolved in 400 cc. of anhydrous acetone, was admixed with 0.5 gram of anhydrous p-toluenesulfonic acid, and the resulting reaction mixture Was allowed to stand at room temperature for 24 hours. Following this reaction period the reaction mixture was diluted with water and extracted with methylene dichloride. The resulting extract was Washed with aqueous sodium bicarbonate solution and then with water until neutral, then dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the residue from acetone/hexane gave 3-methoxy-l9-nor-A -pregnatrien-1la-ol-2O-one.

By repeating this procedure in every detail but one, namely, replacing 3 methoxy l9 nor A pregnatetraen20-one with the corresponding l-methyl steroid, 1-methy1-3-methoxy-l9-nOr-A -pregnatrien- 11a-ol-20-one was obtained.

Example XVII A mixture of 6.6 grams of 3-methoxy19-nor-A pregnatrien-lla-ol-20-one, 2.7 grams of p-toluenesulfonic acid and 300 cc. of acetic anhydride was slowly distilled for 5 hours. Following this reaction period the reaction mixture was cooled, diluted with water and extracted with diethyl ether. The thus-obtained extract was washed with an aqueous sodium bicarbonate solution and then with water until neutral, then dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure, thus giving 3-methoxy-l9-nor-A -pregnatetraene-1la,20-diol 11,20-diacetate, which was used in the next step without further purification.

Six grams of this crude diacetate were admixed with 1.1 molar equivalents of perbenzoic acid in benzene solution, and the resulting reaction mixture was allowed to stand at room temperature in the dark for 20 hours. Following this reaction period the reaction mixture was diluted with water and the organic layer was separated, washed with aqueous sodium bicarbonate and then with water until neutral, then dried over anhydrous sodium sulfate and evaporated to dryness.

The resulting crude 17,29-oxido compound was treated with 50 cc. of a 1/ methanolic potassium hydroxide solution, and the resulting reaction mixture was allowed to stand at room temperature for 1 hour. Following this reaction period the reaction mixture was neutralized with acetic acid, then concentrated to a small volume under reduced pressure. Next, the product was precipitated by the addition of ice water, and was removed by filtration, washed with water and dried. Recrystallization from acetone/methanol gave 3-methoxy-19-n0r-A -pregnatriene-ll'a,17a-diol-20-one.

This procedure was then repeated using 1-methyl-3- methoxy-19-nor-A -pregnatrien-11a-ol-20-one as the steroid starting material, thus giving l-methyl-3-methoxyl9-nor-A -pregnatriene1lot,17a-diol-20-one.

Example XVIII Example XIX A solution of 4 grams of 3-methoxy-20-cycloethylenedioxy-19-nor-A -pregnatriene-11a,l7a-diol in cc.

of pyridine was added to a mixture of 4 grams of chrom'iurn 't'r'ioxide in 80 cool? pyridine, and the resulting reaction mixture was. allowed to stand at room temperatlIQ Qvornight. Following this reaction period the reaction mixture was diluted with ethyl acetate, then filtered through Celite. The filtrate was thoroughly washed with Water, then dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from actone/ hexane gave B-methoxy 20 cycloethylenedioxy-l9-n0r- A -pregnatrien-l7a-ol-1l-one.

By repeating this procedure using l-methyl-B-methoxy- 20 cycloethylenedioxy-19-norA -pregnatriene-11a, 17a-diol as the steroid starting material, 1-methyl-3- methoxy 20-cycloethylenedioxy-19-nor-A -pregnatrien-l7a-ol-l1-one was obtained.

Example XX 3 methoxy 20-cycloethylenedioxy-19-nor-A pregnatrien-lh-ol-ll-one and l-methyl-3-rnethoxy-20- cycloethylenedioxy 19-nor-A -pregnatrien-1711-01- ll-one were isomerized, using methanolic potassium hydroxide in the manner described in Example VIII hereinabove, thus giving 3-methoxy-20-cycloethylenedioxy-l9- nor-9fl-A -pregnatrien-17a-ol-1l-one and l-methyl- 3 methoxy 20-cycloethylenedioxy-19-nor-9/3-A pregnatn'en-lh-ol-l l-one.

Example XXI 3 methoxy-ZO-cycloethylenedioxy-19-nor-9flA pregnatrien-17u-ol-1l-one and 1-methy1-3-methoxy-20- cycloethylenedioxy 19 nor-Qfl-A -pregnatrien-17aol-l l-one were subjected to the Woltl-Kishner reaction in the manner described in Example IX hereinabove, thus giving 3-meth0xy-20-cyclothylenedioxy-19-nor-9fi- A -pregnatrien-17a-ol and l-methyl-3-methoxyl-3- methoxy 20 cycloethylenedioxy 19-nor 9fi-A pregnatrien-Ua-ol.

Example XXII 3 methoxy-ZO-cycloethylenedioxy-19-n0r-9p-A pregnatrien-lh-ol and l-methyl-3-methoxy-20-cycloethylenedioxy 19 nor-9p-A -pregnatrien-l7a-ol were treated with lithium in liquid ammonia in the manner described in Example X hereinabove, thus giving 3-methoxy 20 cycloethylenedioxy-19-nor-9p-A -pregnadien-17a-o1 and 1-methyl-3-methoxy-20-cycloethylenedioxy-l9-nor-9B-A -pregnadien-l7a-ol.

Example XXIII 3 methoxy 20-cycloethylenedioxy-l9-nor-9;8A pregnadien-17a-ol and 1-methyl-3-methoxy-20-cycloethylenedioxy-l9-nor-9fi-A -pregnadien-17a-ol were hydrolyzed in the manner described in Example XI hereinabove, thus giving l9-nor-9/3,1Oa-A -pregnen-17aol-3,20-dione and la-methyl-19-nor 9p,1Oa-A -pregnen- 17u-ol-3,20-dione.

ExampleXXIV 3 methoxy-2O-cycloethylenedioxy-19-nor-9fl-A pregnatrien-ll-one and 1-methyl-3-methoxy-20-cycloethylenedioxy-19-nor-9,8-A -pregnatrien-1 l-one were treated with lithium aluminum hydride in tetrahydrofuran in the manner described in Example XII hereinabove, thus giving mixtures of the corresponding 11aand llfl-ols, i.e., 3 methoxy-20-cycloethylenedioxy-l9-nor-9 8-A pregnatriene-ll(a and i 17a-diol and 1-methyl-3- methoxy 2O cycloethylenedioxy 19-nor-9B-A pregnatriene-llfix and ,3), l7a-di0l.

Example XXV By repeating the procedure of Example X hereinabove using the mixtures of 1104- and llfl-ols prepared as described in Example XXIV hereinabove, the corresponding A dienes, namely, 3-methoxy-20-cycloethylenedioxyl9-nor-9fl-A -pregnadiene-11(a and 18), 170c-di0l and l methyl 3-methoxy ZO-cycloethylenedioxy-l9-nor-9fl- A -pregnadiene-11(a and fi),l7x-diol, respectively, were obtained.

Example XXVI By repeating the procedure of Example XI hereinabove using the mixtures of A -dil1C-11(oc and {3),17a-diols 18 prepared as described in Example XXV hereinabove as the steroid starting materials, the corresponding 19-nor- 9 8,100; steroids, namely, l9-nor-9fi,10a-A -pregnene-11a,

17a-diol-3,20'-dione and 19-nor-9,B,l0u-A -pregnene-l1B, 17a diol 3,20-dione, and la-methyl-l9-nor-9p,l0 a-A pre-gnene-l1a,l7u-diol-3,2041ione and 1a-methyl-l9-nor- 9B, 1 Oa-A pregnene-l 1,9, 1 7oldlOl-3,20di01'16, respectively, were obtained, and these mixtures were then separated into the individual 1111- and llfi-ols by chromatography on alumina.

Example XX VII To a solution of 2 grams of 19-nor-9[3,10a-A -pregnenl7u-ol-3,20-dione in 40 cc. of anhydrous benzene there were added 400 mg. of p-toluenesulfonic acid and 4 0c. of acetic anhydride, and the resulting reaction mixture was allowed to stand at room temperature for 24 hours. Following this reaction period the reaction mixture was poured into ice water and stirred to eifect hydrolysis of excess acetic anhydride. Next, the benzene layer was separated, washed with an aqueous 10% sodium carbonate solution and then with water, then dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the residue from diethyl ether/hexane gave 19-nor-9fi, lOa-A regnadiene-3 l 7a-diol-20-one 3,17-diacetate admixed with a minor amount of 19-nor-9 3,10a-A -pregna diene-3,l7a-diol B-aeetate.

One gram of the thus-obtained mixture was dissolved in 50 ml. of methanol and admixed with 1 ml. of concentrated hydrochloric acid, and the resulting reaction mixture was then refluxed for 2 hours. Following this reaction period the reaction mixture was cooled, neutralized with aqueous sodium bicarbonate solution and diluted with water. The resulting precipitate was collected by filtration, washed with water and dried. Chromatography on alumina followed by recrystallization from diethyl ether/hexane gave l9-nor-9/3,lOa-N-ptegnen-17a-ol-3,20- dione 17-acetate.

By repeating this procedure in every detail but one, namely, replacing acetic anhydride with propionic, caproic and enanthic anhydrides, the corresponding 17-propionate, -caproate and -enanthate of 19-nor-9,8,l0a-A -pregnenl7a-ol-3,20-dione were obtained.

Similarly, by replacing 19-nor-9/3,l0a-A -pregnen-17aol-3,20dione with 1a-methyl-l9-nor-9fi,l0a-A -pregnenl7a-ol-3,20-dione and using each of the anhydrides mentioned hereinabove, the 17-acetate, -propionate, -caproate and -enanthate of la-methyl-l9-nor-9fi,l0a-A -pregnenl70c-Ol-3,20dl0116 were obtained.

Example X X VIII l9-nor-9/3,l0a-A -pregnene-llp,17a-diol-3,20-dione was acetylated with acetic anhydride in benzene solution in the presence of p-toluenesulfonic acid, and the resulting acetylated mixture was hydrolyzed in methanolic concentrated hydrochloric acid, each of these reactions being carried out in the manner described in Example XXVII hereina-bove, to give l9-nor-9fl,10a-A -pregnene-11,9,17adiol-3,20-dione ll,l7-diacetate.

Two grams of the thus-obtained 11,17-diacetate were dissolved in 50 cc. of methanol and admixed with 5 cc. of an aqueous 4% solution of potassium hydroxide. The resulting reaction mixture was then stirred for 1 hour at 0 C. under an inert nitrogen atmosphere. Following this reaction period the reaction mixture was neutralized with acetic acid and the methanol distilled off under reduced pressure. The resulting residue was triturated with water and the solid was then collected by filtration, washed with water and dried. Recrystallization from ethyl acetate/ methanol gave l9-nor-9,8,l0a-A -pregnene-11 3,l7a-diol- 3,20-dione 17-acetate.

By repeating this procedure in every detail but one,

Similarly, by replacing l9-nor-9fi,lfla-M-pregnene-l1B, 17cc diol-3,20-dione with lot-methyl-19-nor-9B,1Oa-A pregnene-l1,8,17a-diol-3,20-dione and using each of the anhydrides mentioned hereinabove, the corresponding 17- acetate, -propionate, -caproate and -enanthate of lot-methyl 19 nor 9fl,1Oa-A -pregnene-11;8,17a-diol-3,20-dione were obtained.

Example XXIX 19 nor 913,100: M-pregnene-l15,17a-diol-3,20dione l7-acetate and lot-methyl-l9-nor-A -pregnene-l15,170:- clione 17-acetate were oxidized, using 8 N chromic acid in acetone solution in the manner described in Example VII hereinabove, thus giving 19-nor-9B,10u-A -pregnen- 17a-ol-3,11,20-trione l7-acetate and 1a-methyl-19-nor- 913,10a-A -pregnen-17a-ol-3,11,20-trione 17-acetate respectively.

By repeating this procedure using the 17-propionates, -caproates and -enanthates prepared as described 1n Example XXVIII hereinabove as the steroid starting materials, the corresponding 11-ones, namely, 19-nor-9B,10u- A -pregnen-17a-ol-3,11,2O-trione l7-propionate, 19-nor- 9K3,1Om-A -pregnen-17wol-3,11,2O-trione 17-caproate, 19- nor-9,8,1Oa-A -pregnen-17a-ol-3,11,20-trione 17-enanthate, 1a methyl 19-nor-9/3,10a-A -pregnen-17a-ol-3J1,20-trione 17-propionate, 1a-methyl-19-nor-9B,IOa-A pregnen- 17a-ol-3,11,20-trione 17-caproate, and 1a-methyl-19-nor- 95,100: A -pregnene-17a-ol-3,11,20-trione 17-enanthate, respectively, were obtained.

Example XXX A solution of 0.17 gram of potassium hydroxide in 0.2 cc. of water and 2.5 cc. of methanol was added, with stirring over a 30 minute period, to a boiling solution of 1 gram of 19 nor 95,100: A -pregnen 17a-ol-3,11,20- trione 17-acetate in 30 cc. of methanol, contained under an inert nitrogen atmosphere, and boiling was then continued for 2 hours. Following this reaction period the reaction mixture was cooled to room temperature, neutralized with acetic acid and concentrated under reduced pressure. The addition of water to the concentrate, followed by crystallization of the precipitated solid from acetone/hexane, gave 19 nor-93,10a-A -pregnen-17a-ol- 3,11,20-trione.

By repeating this procedure using 10: methyl 19-nor- 9,8,10a-A -pregnen 17a ol-3,11,20-trione 17-acetate as the steroid starting material, lamethyl 19 nor-9fl,10a- A -pregnen-17a-ol-3,11,20-trione was obtained.

Example XXXI 17B acetyl A -estratetraen 3-01 and 1- methyl 17B-acetyl-A -estratetraen-3-ol were treated with ethylene glycol in benzene solution in the presence of p-toluenesulfonic acid in the manner described in Example V hereinabove, thus giving 20-cycloethylenedioxy-19-nor-A -pregnatetraen 3 01 and 1- methyl 20 cycloethylenedioxy 10 nor A1Y315(1),9(11)- pregnatetraen-3-0l, respectively.

Example XXXII The ZO-ketals prepared as described in Example XXXI hereinabove were treated with diborane and then with alkaline hydrogen peroxide in the manner described in Example VI hereinabove, thus giving 20-cycloethylenedioxy-19-nor 11113500) pregnatriene 3,11a diol and lot methyl 20 cycloethylenedioxy 19-nor-A pregnatriene-3,11a-diol, respectively.

Example XXXIII The 20-cycloethylenedioxy 3,11a-diols prepared as described in Example XXXII hereinabove were hydrolyzed, using p-toluenesulfonic acid in acetone, in the manner described in Example XVI hereinabove, thus giving 19 nor A pregnatriene 3,11a diol-20-one and 1 methyl 19 nor A pregnatriene-3,11adil-20-0ne. respectively.

By subjecting the thus-obtained 20-ones to the remaining reactions described in Example XVI hereinabove, l9- nor-A pregnatriene 3,11oc,17ot triol-20-one and 1 methyl 19 nor A pregnatriene 3,11ut,17atriol-ZO-one, respectively, were obtained.

Example XXXIV The 3,11a,17a-triol-20-ones prepared as described in Example XXXIII hereinabove were treated with ethylene glycol in benzene solution in the precense of p-toluenesulfonic acid in the manner described in Example V hereinabove, thus giving 20 cycloethylenedioxy 19 nor- A pregnatriene 3,1la,17ot-t1i01 and l-methyl-ZO- cycloethylenedioxy 19 nor A pregnatriene- 3,1la,17a-triol, respectively.

Example XXXV One gram of 20 cycloethylenedioxy 19-nor-A pregnatriene 3,1la,17a-triol in ml. of an aqueous 10% solution of sodium hydroxide was admixed, at room temperature with stirring, with 20 molar equivalents of benzoyl chloride. The resulting precipitate was collected by filtration, washed with water until neutral and recrystallized trom acetone/hexane, thus giving ZO-cycloethylenedioxy 19 nor A -pregnatriene-3,1111,170:- triol 3-benzoate.

By repeating this procedure using l-methyl 20-cycl0- ethylenedioxy 19 nor A -pregnatriene-3,11a,17atriol as the steroid starting material, l-methyl 20-cycloethylenedioxy 19-nor A pregnatriene-3,11a17atriol 3-benzoate was obtained.

Example XXXVI The 3-benzoates prepared as described in Example XXXV hereinabove were oxidized with chromium trioxide in pyridine in the manner described in Example XIX hereinabove, thus giving 20 cycloethylenedioxy-19- nor A pregnatriene-3,17a-diol-1l-one 3-benzoate and l-methyl 20 cycloethylenedioxy-19-nor-A pregnatriene-B,l7a-diol-l1-one 3- benzoate, respectively.

Example XXXVII The ll-ones prepared as described in Example XXXVI hereinabove were isomerized in the manner described in Example VIII hereinabove, thus giving ZO-cycloethylenedioxy 19 nor 9fi-A pregnatriene3,17a-diolll-one and l-methyl 20 cycloethylenedioxy 19-nor- 9;? A -pregnatriene-Zi,17a-diol-1l-one, respectively.

Example XXXVIII compounds prepared as described in Example XX hereinabove.

Example XXXIX A solution of 1.6 grams of Got-methyl-19-nor-9;3,10a-A pregnene-17a,21-diol-3,20-dione in 8 cc. of pyridine was cooled to O C., then admixed with 0.8 gram of tosyl chloride. The resulting reaction mixture was held at 0 C. for 16 hours, then diluted with 100 cc. of chloroform, washed successively with dilute hydrochloric acid, water, aqueous sodium bicarbonate solution and again with water, then dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure, thus giving the crude 21-tosylate of 6a-methyl-19-nor-9B,1Oa-A pregnene-17a, 21-diol -3,20-dione.

A solution of 1.5 grams of the above-prepared crude 21-tosylate in 60 cc. of glacial acetic acid was admixed with 4 grams of sodium iodide, and the resulting reaction mixture was then refluxed for 2 hours. Following this reaction period the reaction mixture was poured into ice water and extracted several times with methylene dichloride. The extracts were then combined, washed with an aqueous sodium carbonate solution, then with an aqueous sodium sulfite solution and finally with water, then dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Crystallization of the resulting residue from acetone/ hexane gave 6a-methyl-l9- Example XL The 17a-hydroxy-21-desoxy steroids prepared as described in Example XXIX hereinabove were esterified with acetic, propionic, cyclopentylpropionic, caproic, enanthic and undecenoic anhydrides in the manner described in Example XXVII hereinabove, thus giving the corresponding 17-acetates, -propionates, -cyclopentylpropionates, -caproates, -enanthates and -undecenoates.

Example XLI A solution of 1 gram of 6a-methyl-l9-nor-9p,IDs-A pregnen-l7u-ol-3,20-dione in 80 cc. of 80% acetic acid was admixed with 50 grams of zinc dust, and the resulting reaction mixture was refluxed for hours. Following this reaction period the zinc was removed by filtration and the filtrate was then diluted with water. The thusformed precipitate was collected by filtration, washed with water and then crystallized with hexane/diethyl ether, thus giving 6ot-methyl-l9-nor-9fi,l0a-A -pregnene- 3,20-dione.

By repeating this procedure using the remaining 170:- hydroxy-21-desoxy steroids obtained as described in EX- ample XXXIX hereinabove as the steroid starting materials, the corresponding 17-desoxy compounds, namely, 16u-methyl-l9-nor-9fl,lOm-M-pregnene 3,20 dione, 16B- methyl-l9-nor-9/S,lOa-M-pregnene 3,20 dione, 6,160:- dimethyl-19-nor-9fl,10u A pregnene 3,20 dione, and 6tx,l6,B-dimethyl l9 nor-913,10a-A -pregnene-3,20-dione, respectively, were obtained.

Example XLII The following solutions A, B and C were prepared using distilled water as the solvent.

Solution A was prepared by mixing 425 cc. of a 1.742% dipotassium hydrogen phosphate (K HPOQ solution with 75 cc. of a 1.38% monosodium dihydrogen phosphate (NaH PO solution.

Solution B was prepared by diluting a mixture of 1 liter of a 4.5% sodium chloride solution, 40 cc. of a 5.75% potassium chloride solution and 10 cc. of a 19.1% magnesium sulfate solution to a volume of 5 liters.

Solution C was prepared by dissolving 20.9 grams of furnaric acid and 14.4 grams of sodium hydride in 1 liter of water and then diluting the solution to 1.2 liters.

Then, 475 cc. of solution A, 4.32 liters of solution B and all of solution C were mixed.

Defatted adrenal glands of recently slaughtered cattle were ground in a meat grinder until a homogeneous mass was obtained. To 1 kilogram of this homogeneous mass there was then added, with vigorous stirring, 2 liters of the mixture of solutions A, B and C, followed by 1 gram of 6a methyl l9 nor-918,l0a-A -pregnene-3,20-dione dissolved in 5.35 parts by weight, based on the weight of the steroid, of propylene glycol. The resulting mixture was stirred at 37 C. for 3 hours, following which 13 liters of acetone were added and the mixture was stirred at room temperature for an additional hour. At this point, the acetone extract was separated by filtration, the filter cake was washed with 6 liters of acetone, the washings were combined with the filtrate, and the solvent was then removed by distillation under reduced pressure. Chromatography on alumina followed by crystallization of the solid fractions from methylene dichloride/ acetone gave 60:- methyl-l9-nor-9fl,l-Oa-Af -pregnen-l 1B-ol-3,20-dione.

By repeating this procedure using the remaining 17- desoxy compounds prepared as described in Example XXXI hereinabove as steroid starting materials, the corresponding llfi-hydroxy steroids, namely, 16a-methyl-l9- nor-9;8,10a-A -pregnen-1 1fi-ol-3,20-dione, l6fi-methyl-19- nor-9p,10a-A -pregnen 11p ol 3,20 dione, 60,l6adimethyl-19-nor-9,8,10a-A -pregnen-1 1fi-ol-3,20-dione, and 60;,166 dimethyl-19-nor-9fl,10ot-A -pregnen-1Idol-3,20- dione, respectively, were obtained.

Example XLIII The llfi-hydroxy steroids prepared as described in Example XLII were oxidized, using 8 N chromic' acid in acetone solution in the manner described in Example VII hereinabove, thus giving 6u-methyl-19-nor-9fi,10a-A pregnene 3,11,20 trione, 16'a-methyl-19-nor-9/8,10a-A pregnene 3,11,20 trione, l6 3-methyl-19-nor-9fi,Illa-A pregnene 3,11,20-trione, 6a,16a dimethyl-19-nor-9fl,10d- A -pregnene-3,l1,20,-trior1e, and 6a,16 8-dimethyl-19-nor- 9 3, 1 0a-A -pregnene-3,l 1,20-trione, respectively.

Example X LV The 11,8,17a dihydroxy-Zl-desoxy steroids prepared as described in Example XLIV hereinabove were esterified 'with acetic, propionic, cyclopentylpropionic, caproic, en-

anthic and undecenoic anhydrides in the manner described in Example XXVIH hereinabove, thus giving the corresponding 17-acetates, -propionates, -cyclopentylpropionates, -caproates, -enanthates and -undecenoates, respectively.

Example XLIV 6u-methyl-l9-nor-9B, l 0a-A -pregnene-l 1,8,17a-diol-3,

ZO-dione 17-acetate; 16a-methyl-19-nor-9B, 1 0a-A -pregnene-l 113,17a-di0l-3 20-dione 17-acetate; 16fl-methyl-19-nor-9B,10a-A -pregnene-l'1 3,17a-diol- 3,20-dione 17-acetate;

23 6a,16a-dimethyl-19-nor-9B,10a-A -pregnene-115,

17OL-dlO1-3,20-Cli01'1 17-acetate and 60c, l6 8-dimethyl-l9-nor-9p,10a-A -pregnene-1113,17a-di01-3, 20-dione 17-acetate were oxidized, using 8 N chromic acid in acetone solution in the manner described in Example VII hereinabove, thus giving 6a-methyl- 1 9-nor-9 ,8, 10a-A -pre gnen- 1701-01-3 ,1 1,20-

trione 17-acetate, 16amethyl-19-nor-9fi,10a-A -pregnen-17a-o1-3,11,20-

trione 17-acetate, 16/3-methy1-l9-nor-9fi,lOa-A -pregnen-17a-ol-3,l 1,

20-trione 17-acetate, 6a, l6a-dimethyl-l9-nor-9B, 10a-A -prcgnen-17a-0l-3 11,20-trione 17- acetate, and 6a,l6fi-dimethyl-19-nor 9 3,10oi-A -pregnen-1711-01-3,

11,20-tri0ne 17-acetate, respectively.

Example XLVII The 11-0ne-l7-acylates prepared as described in Example XLVI hereinabove were hydrolyzed in the manner described in Example XXX hereinabove, thus giving 16a-methyl-19-nor-9/8,10a-A -pregnen-17a-o1-3,11,20-

trione,

16fi-rnethyl-19-nor-9B,10a-A -pregnen-17a-0l-3J 1,20-

trione,

6m16a-dimethyl-19-nor-9fi,10a-A -pregnen-17a-ol-3,

11,20-tri0ne, and

6m,16,3-dimethyl-10-noF9fi, 10a-A -pregnen-17a-0l-3,

11,20-trione, respectively.

It will be obvious to those skilled in the art that other changes and variations can be made in carrying out the present invention without departing from the spirit and scope thereof as defined in the appended claims.

We claim:

1. 19-nor-9p8,l0a-A -pregnen-17a-ol-3J1,20-trione.

2. 6a,16m-din1ethyl-19nor-9fi,10a-A -pregnene-3,20- dione.

3. 6m-methyl-19-n0r-9B,10a-A -pregnen-17a-ol-3, ZO-dione.

4. 6a-methy1-19-nor-9B,10a-A -pregnen-17a-0l-3, ZO-dione 17- acetate.

5. 60:,16a-dimethyl-l9-nor-9/3,10a-A -pregnen-17a- 01-3,20-dione.

6. 6a,16a-dimethyl-19-nor-9fi,l0a-A -pregnen-l7u-ol- 3,20-dione 17-acetate.

7. 6a-methyl-19-uor-9fl,1Oa-A -pregnen-1 15-01-3, 20-di0ne.

8. 6a-rnethyll9-nor-9 8, l0ot-A -pregnene-3 ,1 1,20- trione.

9. 6a-methy1-19-nor-9fi,10ot-A -pregnene-1 15,170:- diol-3,20-di0ne.

10. Get-methyl-19-n0r-9fi,1Oa-A -pregnen-17m-o1-3, 11,20-trione.

References Cited UNITED STATES PATENTS 3,198,792 8/1965 Reerink et a1. 260-239.55

ELBERT L. ROBERTS, Primary Examiner. 

2. 6A, 16A-DIMETHYL-19NOR-9B,10A-$4-PREGNENE-3,20DIONE. 